OVERALL DESCRIPTION (adapted from applicant's abstract): The long-term and overall goal of this program project is to use molecular genetic as well as immunological approaches to enhance the acceptability of cellular transplants. Specifically, the applicants will focus on two models of transplantation: keratinocyte and islet transplants. The former is important for a large number of patients suffering from unhealed wounds as well as severe burns, while the second has increasingly been considered for treating diabetic patients. However, both procedures are frequently plagued by graft rejection. The central goal of these three projects is to determine if tolerance can be induced using a combination of genetic manipulations and gene therapy approaches. Accordingly, the first project plans to examine the role of class II MHC genes as well as associated antigen presenting molecules in triggering immune response against keratinocyte as well as islet cell transplants. Specifically, gene knockout (GKO) mice bearing defects in various stages of class II antigen presentation will be used as donor tissues to assess the role of these molecules in both allogeneic and xenogeneic transplants. In addition, cells derived from GKO mice will be tested for the capacity to induce tolerance. In a second project, focus will be placed on the NOD mouse model with specific emphasis on the utilization of "immune deviation" to enhance tolerance and to increase transplant acceptance. Specifically, the generation of T cells that are tolerant to pancreatic antigens will be tested. In addition, a gene therapy approach is proposed to use deoxyribonucleic acid (DNA) vaccines to introduce pancreatic genes to tolerize animals, in order to enhance the acceptance of islet cell transplants. In the final project, the focus is a model where tolerance against non-specific peptides can lead to specific tolerance of transplanted tissues. Focus will be placed on peptides that bind class I MHC molecules which are frequently a major culprit in transplant rejection. Together, these three projects address different aspects of induction tolerance to two specific cellular transplants. Significant collaborations and synergy are planned.